A flurry of startling discoveries in stem cell biology in past months has shattered preconceptions about how cell specialization is controlled in the body and has boosted the field to the top of scientific, political and commercial agendas. The excitement has raised hopes that the long-sought goal of being able to regenerate human tissues may be closer than had been thought.
Stem cells can replicate indefinitely and can also give rise to more specialized tissue cells when exposed to appropriate chemical cues. Embryonic stem cells, which are derived from the earliest developmental stages of an embryo and can spawn almost all types of cells in the body, hit the headlines last November, when James A. Thomson of the University of Wisconsin described his isolation of human versions. John D. Gearhart of Johns Hopkins University published at about the same time a report that he had isolated similar human cells, called embryonic germ cells, from the developing gonads of fetuses; he is now making progress in turning the cells into specific tissue types. Since then, more remarkable results have been disclosed, particularly with more specialized stem cells. Such cells lack the complete developmental flexibility of embryonic stem cells but can still give rise to a useful variety of cells.
The most impressive findings have come from animal work on neural stem cells, which are derived from the fetal brain and seem likely to exist in the adult brain, too. They grow readily in culture--unlike some other specialized stem cells--and can form all the types of cells normally found in the brain. Thus, they may be able to repair damage caused by Parkinson's disease and other neurological conditions. Evan Y. Snyder of Harvard Medical School and his colleagues have demonstrated that human neural stem cells respond appropriately to developmental cues when introduced into the brains of mice; they engraft, migrate and differentiate the way mouse cells do. Moreover, they can produce proteins in a recipient brain in response to genes that were artificially introduced into the donor cells.
Ronald D. G. McKay of the National Institute of Neurological Disorders and Stroke says it seems the same control systems that regulate specialization of cells in a fetus continue to operate in adults, making prospects for brain repair seem realistic. McKay's experiments indicate that neural stem cells placed in a rodent brain can form neurons and make synapses of types appropriate to their location, an indication they are functional.
Neural stem cells also seem to have a previously unsuspected developmental flexibility. Earlier this year Angelo L. Vescovi of the National Neurological Institute in Milan and his colleagues showed that neural stem cells can form blood if they are placed in bone marrow. Vescovi says that if other stem cell types can also modify their fates in this surprising way "you are looking at a reservoir of cells in the adult that can regenerate all tissue types." Other clues that stem cells are flexible about their fates have emerged: Darwin Prockop of MCP Hahnemann University in Philadelphia has found that human bone marrow stromal cells, a type that had been thought to have nothing to do with nerve tissue, can form brain tissue when implanted into rat brains. And Bryon E. Petersen of the University of Pittsburgh and his associates demonstrated recently that stem cells from bone marrow can regenerate the liver.
Embryonic stem cells could be the most powerful ones of all, but only a small group of investigators is working with them, because at present only private funds are available. The National Institutes of Health has, in a controversial decision, announced that it will support scientists who want to work with established embryonic stem cell lines--but not investigators who want to establish the lines in the first place, because the process entails killing an embryo and so would contravene a congressional ban.
Although some 70 legislators have objected to the NIH decision, the agency is now drawing up guidelines to govern the work. They require that the cell lines must have been derived from freely donated spare embryos resulting from treatment of infertility, not from embryos created specifically for research. In late May the National Bioethics Advisory Commission was set to issue yet more liberal recommendations. It favors federal grants for scientists both to experiment with and to derive embryonic stem cells from abandoned embryos, a shift that would mean lifting the congressional ban on most embryo research.
Medical applications of embryonic stem cells will probably require cells that are genetically matched to the patient, so as to avoid rejection. Nuclear transfer, the central technology of cloning, could in principle provide matched cells, because a cloned embryo derived from a patient's cell sample could yield embryonic stem cells. Yet there could still be show-stoppers. It may turn out that embryonic stem cells descended from cloned embryos lack the full potential of those from natural embryos, for example. Indeed, many embryos resulting from nuclear transfer have defects, possibly because gene expression is abnormal in embryos that lack two genetic parents.
In an attempt to avoid the need to create embryos, Geron Corporation in Menlo Park, Calif., which has supported most of the work on embryonic stem cells to date, recently formed a $20-million alliance with the Roslin Institute near Edinburgh, home of Dolly the cloned sheep, and bought a spin-off company, Roslin Bio-Med. The objective is to study how the institute's cloning procedure succeeds in reprogramming adult cells so they can form multiple tissues. If successful, Geron might then be able to make stem cells of any type from adult tissue without the need for a donated egg and without the ethical complications of creating a cloned embryo.
Advanced Cell Technology in Worcester, Mass., is pursuing a different strategy: Michael D. West, the company's president, says he has preliminary indications that he can make human embryonic stem cells by fusing adult human cells with a cow's egg. But some scientists are skeptical, because embryos generally cannot develop if cells contain components from such different species. West, however, promises publication of dramatic results soon. The race toward the long-sought goal of human tissue regeneration may be entering its most exciting phase.